Allylpalladium Complexes Research Articles

Catalytic Decarboxylative Asymmetric Allylic Alkylation for the Synthesis of Axially Chiral Biaryls

AbstractHerein, we report a palladium‐catalyzed atroposelective decarboxylative asymmetric allylic alkylation. A chiral palladium complex with a phosphoramidite ligand effectively desymmetrizes biaryls containing cinnamyl carbonate with excellent enantioselectivities. The addition of a catalytic amount of base accelerates the reaction process without loss of enantioselectivity. Cross‐over experiment provides mechanistic insight, suggesting that allyl palladium complex primarily dissociates from the original biaryl substrate and deliver allyl species intermolecularly. Analysis of product distribution at various time points indicates that secondary kinetic resolution plays a crucial role in achieving remarkable atroposelectivity.

Palladium-Catalyzed Fluorinative Bifunctionalization of Aziridines and Azetidines with gem-Difluorocyclopropanes.

An unprecedented Pd-catalyzed fluorinative bifunctionalization of aziridines and azetidines was successfully developed via regioselective C-C and C-F bond cleavage of gem-difluorocyclopropanes, leading to various β,β'-bisfluorinated amines and β,γ-bisfluorinated amines. This reaction was achieved by incorporating a 2-fluorinated allyl group and a fluorine atom scissored from gem-difluorocyclopropane in 100% atom economy for the first time. The mechanistic investigations indicated that the reaction underwent amine attacking 2-fluorinated allyl palladium complex to generate η2-coordinated N-allyl aziridine followed by fluoride ligand transfer affording the final β- and γ-fluorinated amines.

Palladium‐Catalyzed Fluorinative Bifunctionalization of Aziridines and Azetidines with gem‐Difluorocyclopropanes

AbstractAn unprecedented Pd‐catalyzed fluorinative bifunctionalization of aziridines and azetidines was successfully developed via regioselective C−C and C−F bond cleavage of gem‐difluorocyclopropanes, leading to various β,β′‐bisfluorinated amines and β,γ‐bisfluorinated amines. This reaction was achieved by incorporating a 2‐fluorinated allyl group and a fluorine atom scissored from gem‐difluorocyclopropane in 100 % atom economy for the first time. The mechanistic investigations indicated that the reaction underwent amine attacking 2‐fluorinated allyl palladium complex to generate η2‐coordinated N‐allyl aziridine followed by fluoride ligand transfer affording the final β‐ and γ‐fluorinated amines.

Combined Treatment of Cancer Cells Using Allyl Palladium Complexes Bearing Purine-Based NHC Ligands and Molecules Targeting MicroRNAs miR-221-3p and miR-222-3p: Synergistic Effects on Apoptosis.

Combined treatments employing lower concentrations of different drugs are used and studied to develop new and more effective anticancer therapeutic approaches. The combination therapy could be of great interest in the controlling of cancer. Regarding this, our research group has recently shown that peptide nucleic acids (PNAs) that target miR-221 are very effective and functional in inducing apoptosis of many tumor cells, including glioblastoma and colon cancer cells. Moreover, in a recent paper, we described a series of new palladium allyl complexes showing a strong antiproliferative activity on different tumor cell lines. The present study was aimed to analyze and validate the biological effects of the most active compounds tested, in combination with antagomiRNA molecules targeting two miRNAs, miR-221-3p and miR-222-3p. The obtained results show that a "combination therapy", produced by combining the antagomiRNAs targeting miR-221-3p, miR-222-3p and the palladium allyl complex 4d, is very effective in inducing apoptosis, supporting the concept that the combination treatment of cancer cells with antagomiRNAs targeting a specific upregulated oncomiRNAs (in this study miR-221-3p and miR-222-3p) and metal-based compounds represents a promising therapeutic strategy to increase the efficacy of the antitumor protocol, reducing side effects at the same time.

Atroposelective desymmetrization of 2-arylresorcinols via Tsuji-Trost allylation

Palladium-catalyzed asymmetric allylic alkylation has proven to be a powerful method for the preparation of a wide variety of chiral molecules. However, the catalytic and atroposelective allylic alkylation is still rare and challenging, especially for biaryl substrates. Herein, we report the palladium-catalyzed desymmetric and atroposelective allylation, in which the palladium complex with a chiral phosphoramidite ligand enables desymmetrization of nucleophilic 2-arylresorcinols in a highly enantioselective manner. With the aid of the secondary kinetic resolution effect, a wide variety of substrates containing a hydroxymethyl group at the bottom aromatic ring are able to provide O-allylated products up to 98:2 er. Computational studies show an accessible quadrant of the allylpalladium complex and provide three plausible transition states with intra- or intermolecular hydrogen bonding. The energetically favorable transition state is in good agreement with the observed enantioselectivity and suggests that the catalytic reaction would proceed with an intramolecular hydrogen bond.

Homo‐ and Copolymerization of Norbornene with Allyl Palladium and Nickel Complexes Bearing Imidazo[1,5‐a]pyridine Sulfonate Ligands

AbstractA series of allyl palladium and nickel complexes based on imidazo[1,5‐a]pyridine sulfonate ligands were synthesized. All these complexes were fully characterized by 1H and 13C NMR, elemental analysis, and high‐resolution mass spectrometry (HRMS). By treatment with Me2AlCl, palladium complexes showed high activities (up to 4.5×107 g of PNB (mol of Pd)−1 h−1) in norbornene polymerization, and the steric hindrance of the catalysts had little effect on the catalytic activities. They could also catalyze the copolymerization of norbornene with butyl vinyl ether (BVE) and ester monomers, but could not catalyze the copolymerization of norbornene with allyl butyl ether (ABE). In addition, the catalytic activities of nickel complexes for norbornene polymerization were similar to that of palladium complexes upon activation with MAO. They could catalyze copolymerization of norbornene with BVE and ABE, but not with ester monomers. In nickel system, the lower steric hindrance of the substituent led to higher activity.

Formation of Allylpalladium Complexes and Asymmetric Allylation Involving Modular Bridging Diamidophosphite-Sulfides Based on 1,4-Thioether Alcohols

Formation of Allylpalladium Complexes and Asymmetric Allylation Involving Modular Bridging Diamidophosphite-Sulfides Based on 1,4-Thioether Alcohols

Imidazo[1,5-a]pyridine-3-ylidenes and dipyridoimidazolinylidenes as ancillary ligands in Palladium allyl complexes with potent in vitro anticancer activity

The synthesis and characterization of silver and palladium allyl complexes bearing imidazo[1,5-a]pyridine-3-ylidene and dipyridoimidazolinylidene ligands is reported.NMR analysis of the starting azolium salts revealed the weaker σ-donor character of these NHC ligands compared to the most common imidazol-2-ylidenes and imidazolin-2-ylidenes.All cationic palladium allyl complexes showed remarkable antitumoral activity toward a panel of cisplatin-sensitive and cisplatin-resistant cell lines, with IC50 in the micro- and nano-molar range.Among the tested derivatives, those with a pyridine arm combine good anticancer activity with a poor cytotoxicity against normal cells. Finally, all palladium complexes, especially the bisNHC species, showed good photoluminescence properties, with emission in the blue/green region.

Synthesis, characterization and anticancer activity of palladium allyl complexes bearing benzimidazole-based N-heterocyclic carbene (NHC) ligands

The synthesis of twelve new palladium allyl complexes bearing benzimidazole-based NHC (NHC = N-heterocyclic carbene) ligands is reported. All the complexes were characterized by NMR and elemental analysis and, in the case of complex 5c, it was possible to confirm the connectivity by single crystal X-ray diffraction.The cationic palladium allyl complexes were tested toward 5 different cancer lines, with IC50 values generally lower than cisplatin and similar antiproliferative activity in the two ovarian cancer cell lines (A2780 and A2780cis), suggesting a different mechanism of action from classical platinum-based anticancer drugs.Compounds equipped with a pyridine arm or with the NHC/PTA combination (PTA = 1,3,5-triaza-7-phosphaadamantane) showed a lower cytotoxicity on normal cells with respect to cancer ones.By comparing the IC50 values of mixed NHC/PTA complexes reported in this work and their trifluoromethyl congeners recently published by our group, it appears evident that they have very similar antiproliferative activity against cancer cells but the absence of the CF3 group significantly decreases the selectivity toward them.

C1‐Symmetric Atropisomeric NHC Palladium(II) Complexes: Synthesis, Resolution and Characterization

AbstractSeries of chiral palladium(II) allyl and cinnamyl complexes bearing a C1‐symmetric N‐heterocyclic carbenes were synthesized from achiral precursors. The chirality of theses complexes results from the formation of the carbene‐palladium bond which restricts the rotation of dissymmetric N‐aryl substituents of the NHC and thus creates an axis of chirality. Chiral HPLC at preparative scale enabled the resolution of racemic complexes and provided a straightforward access to complexes with excellent enantiopurities (>99.5% ee). Enantiopure complexes were studied by crystal X‐ray diffraction and electronic circular dichroism (ECD). Their configuration stabilities were investigated both experimentally and theoretically through the determination of the rotational barrier values. These complexes were tested for the intramolecular α‐arylation of amides, with a moderate chiral induction (up to 54% ee).magnified image

A density functional theory study on the mechanism of the allylpalladium-catalyzed dehydrogenation of aldehydes and cyclic ketones

The results of density functional theory calculations at the APFD/SDD level are detailed herein in order to study the main steps in the α,β-dehydrogenation of aldehydes and cyclic ketones in the presence of an allylpalladium complex catalyst. The mechanism is believed to proceed via an allylpalladium enolate complex (A) in equilibrium with the carbon-bonded complex (B), followed by β-hydride elimination to yield the allylpalladium hydride coordinated to the α,β-unsaturated carbonyl (complex C). The optimized structures and detailed energy profiles of these intermediates and their corresponding transition states are presented herein. The results indicate that the intermediates and their transition states are more stable in THF solution than in the gas phase. In detail, the energy barriers for the two steps are found to be 25.22 and 11.13 kcal/mol, respectively, in THF, and 29.93 and 9.77 kcal/mol, respectively, in the gas phase.

Palladium Complexes Based on Ylide-Functionalized Phosphines (YPhos): Broadly Applicable High-Performance Precatalysts for the Amination of Aryl Halides at Room Temperature.

Palladium allyl, cinnamyl, and indenyl complexes with the ylide‐substituted phosphines Cy3P+−C−(R)PCy2 (with R=Me (L1) or Ph (L2)) and Cy3P+−C−(Me)PtBu2 (L3) were prepared and applied as defined precatalysts in C−N coupling reactions. The complexes are highly active in the amination of 4‐chlorotoluene with a series of different amines. Higher yields were observed with the precatalysts in comparison to the in situ generated catalysts. Changes in the ligand structures allowed for improved selectivities by shutting down β‐hydride elimination or diarylation reactions. Particularly, the complexes based on L2 (joYPhos) revealed to be universal precatalysts for various amines and aryl halides. Full conversions to the desired products are reached mostly within 1 h reaction time at room temperature, thus making L2 to one of the most efficient ligands in C−N coupling reactions. The applicability of the catalysts was demonstrated for aryl chlorides, bromides and iodides together with primary and secondary aryl and alkyl amines, including gram‐scale applications also with low catalyst loadings of down to 0.05 mol %. Kinetic studies further demonstrated the outstanding activity of the precatalysts with TOF over 10.000 h−1.

Quantum chemical investigation of the oxidative addition reaction of allyl carboxylates to Ni(0) and Pd(0) complexes

Objectives. The first allylpalladium complex was synthesized and characterized 60 years ago at the Department of Physical Chemistry of M.V. Lomonosov Moscow State University of Fine Chemical Technology (MITHT). This discovery was an important stage in the development of a new direction in chemistry - metal complex catalysis, which subsequently led to understanding the strategy for studying the mechanisms of catalysts action, and gave a powerful impetus to the study of intermediates of catalytic reactions. The key sta.ge in many catalytic processes involving transition metal complexes is the oxidative addition stage. The study’s aim was the quantum chemical modeling of the oxidative addition stage of allylic carboxylates to the Ni(0) and Pd(0) complexes. Methods. Quantum chemical calculations were carried out under the Kohn-Sham method for the density Junctional theory using the PBE exchange-correlation Junctional and all-electron L11 basis set. Results. As a result of theoretical study, we showed that the oxidative addition of allyl acetate to the triisopropylphosphite complex of nickel(0) and allyl formate to the triphenylphosphine complex of palladium(O) can proceed along two routes. In the first of them, in the coordinated breaking of the С - О bond and the formation of the metal-O bond, the same oxygen atom is involved, thus forming a three-center transition state. In the second route, the restructuring of relations is carried out in a five-center transition state. The chelating effect in the five-centered transition state of the second route reduces the reaction’s activation barrier by 12.7 kcal/mol for allyl acetate and the nickel(0) triisopropylphosphite complex Ni(P(QPr) 3 ) 2 and by 9.9 kcal/mol for allyl formate and the palladium(O) triphenylphosphine complex Pd(PPh 3 ). The presence of the second triphenylphosphine ligand in Pd(PPh 3 ) 2 reduces the activation barrier by only 2.6 kcal/mol. Conclusions. The quantum chemical modeling performed allowed us to determine the preference for the oxidative addition of allyl carboxylates to the Ni(0) and Pd(0) complexes through a five-center transition state. The reaction’s activation barriers through the “classical” three-center interaction are 9.9-12.7 kcal/mol higher, and the chelating effect is more noticeable for the Ni complex The presence in the coordination sphere of several bulky ligands, such as triphenylphosphine, practically eliminates the chelating effect in the oxidative addition of allyl carboxylates.

Mixed N-heterocycles/N-heterocyclic carbene palladium(II) allyl complexes as precatalysts for direct arylation of azoles with aryl bromides

A series of mixed N-heterocycles/N-heterocyclic carbene palladium(II) allyl complexes with general formula [(NHC)Pd(η3-allyl)]2(μ2-N-heterocycles)(BF4)2 were prepared in one pot based on anion metathesis of (NHC)Pd(η3-allyl)Cl complexes and then ligand replacement with N-heterocycles [N-heterocycles = pyrazine (pyz), 4,4′-bipyridine (bpy) and trans-4,4′-bipyridylethylene (bpe)]. The solid-state structures shown dinuclear structures with two palladium(II) centers holding together by bridged N-heterocycles. Initially investigation of the obtained complexes as precatalysts for direct CH bond arylation of azoles with aryl bromides was carried out.

From Chelating to Bridging Ligands: N-Sulfonyliminoimidazolium Ylides as Precursors to Anionic N-Heterocyclic Carbene Ligands

The synthesis and investigation of a new family of anionic N-heterocyclic carbene (NHC) ligands, based on N-sulfonyliminoimidazolium ylides, is reported. Their corresponding silver complexes have been synthesized and present distinctive geometries compared to the previously reported ligands derived from the N-acyliminoimidazolium family. A comparison of the two ligand families was performed with palladium(II) allyl complexes to investigate their binding mode preference. The N-sulfonyl derived ligands were found to strongly favor bridging binding instead of chelation. This strong preference was exploited to synthesize a novel copper(I)–palladium(II) heterotrimetallic complex.

Tunable Synthesis of 2-Ene-1,4-diones, 4-Hydroxycyclopent-2-en-1-ones, and 2-(Furan-3-yl)acetamides via Palladium-Catalyzed Cascade Reactions of Allenols.

An efficient and regioselective synthesis of 2-ene-1,4-diones, 4-hydroxycyclopent-2-en-1-ones, or 2-(furan-3-yl)acetamides is successfully realized through palladium-catalyzed one-pot multicomponent reactions of allenols with aryl iodides and carbon monoxide in the presence of tertiary amines. Interestingly, the selectivity depends on the substitution patterns of the allenol substrates. To be specific, from the reaction of allenols with no substituent attached on the internal position of the allenic moiety, 2-ene-1,4-diones or 4-hydroxycyclopent-2-en-1-ones were formed selectively through carbonylation of aryl iodide followed by acylation of allenol with the in situ formed acyl palladium species, β-hydride elimination of the in situ formed allyl palladium complex, and further tautomerization or intramolecular aldol reaction. From the reaction of allenols bearing a substituent at the internal position of the allenic unit, on the other hand, diversely substituted 2-(furan-3-yl)acetamides were formed through a cascade process combining carbonylation of aryl iodide, acylation, and carbonylation of allenol followed by intramolecular condensation and amination by tertiary amine featuring an oxidant-free C-N bond cleavage.

Palladium-Catalyzed Aerobic Homocoupling of Alkynes: Full Mechanistic Characterization of a More Complex Oxidase-Type Behavior

A combined experimental and computational approach has been used to shed light on the mechanism of the Pd-catalyzed oxidative homocoupling of alkynes using oxygen as the oxidant. Mechanistic understanding is important because of the synthetically relevant direct involvement of oxygen in the oxidative coupling and because of the presence of related processes as undesired side reactions in cross-coupling reactions involving terminal alkynes. A low-ligated [Pd(PPh3)(alkyne)] complex is key in the process, and it can be conveniently generated from allylic palladium(II) complexes in the presence of a base or from Pd(I) allylic dimers as precatalysts. The catalytic coupling occurs by alkyne metalation to give an anionic [Pd(PPh3)(alkynyl)]− complex that is then oxidized by oxygen. The interaction with oxygen occurs only on this electron-rich Pd(0) anionic species and leads to a (κO,κO-peroxo)palladium(II) singlet intermediate that undergoes subsequent protonolysis to give a (κO-hydroperoxo)palladium(II) complex...

Synthesis of new allyl palladium complexes bearing purine-based NHC ligands with antiproliferative and proapoptotic activities on human ovarian cancer cell lines.

A series of new palladium allyl complexes bearing purine-based carbenes derived from caffeine, theophylline and theobromine have been prepared and characterized by NMR spectroscopy, and elemental analysis and in two cases by single crystal X-ray diffraction. The cytotoxic and proapoptotic activities of compounds have been determined in vitro on human ovarian cancer A2780 and SKOV-3 cell lines. These experiments have shown that the palladium-allyl fragment induces a general cytotoxicity, but the choice of the supporting ligands is of paramount importance for achieving the best results. In particular complexes 4c, 4d and 5d exhibit a higher antiproliferative effect (IC50: 0.09, 0.81 and 0.85 μM respectively) than cisplatin (IC50: 1.5 μM) on A2780 cells, and 4d (IC50: 1.7 μM vs. 5.94 μM) on SKOV-3 cell line. Moreover in many cases it has been proved that the cytotoxicity of our complexes is associated with the induction of apoptosis.

Synthesis and coordination chemistry of enantiopure t-BuMeP(O)H.

Both enantiomers of the optically pure Secondary Phosphine Oxide (SPO) t-BuMeP(O)H (1) have been obtained by deboronation of phosphinous acid-borane t-BuMeP(O)H·BH3 (3) with HBF4 followed by hydrolysis of the intermediate adduct t-BuMeP(O)H·BF3 (1·BF3), which has been isolated and crystallographically characterised. Complexes [MCl(COD)(κP-(R)-1)] (M = Ir, Rh; 4 and 7 respectively) have been detected in solution but could not be isolated while trans-[RhCl(CO)(κP-(S)-1)2] (9) has been successfully obtained in good yield. Gold complex [AuCl(κP-(S)-1)] (10) has been prepared and its crystal structure shows the presence of aurophilic interactions. Three new ruthenium complexes ([RuCl2(η6-p-cymene)(κP-(R)-1)], 12), ([RuCl2(CO)3(κO-(S)-1)], 13) and trans-([RuCl2(CO)2(κP-(S)-1)2], 14) have been synthesised and fully characterised, including the crystal structure of 12. Four palladium coordination compounds have been prepared: trans-[PdCl2(κP-(S)-1)2] (trans-15), [Pd(μ-Cl)(κP-(S)-1)2]2 (16·OH and 16·BF2) and [Pd(μ-OAc)(κP-(S)-1)2] (17) and the crystal structure of complex 16·OH proves the pseudobidentate coordination of the two molecules of 1. Three organometallic allylpalladium complexes have been prepared namely [Pd(η3-Ph2C2H3)Cl(κP-(S)-1)] (18) and [Pd(η3-Ph2C2H3)(κP-(S)-1)2] (19·OH and 19·BF2). The crystal structure of 19·BF2 constitutes the first allylpalladium-SPO complex reported to date.

Synthesis of novel allyl palladium complexes bearing purine based NHC and a water soluble phosphine and their catalytic activity in the Suzuki‐Miyaura coupling in water

We have synthesized and fully characterized some novel allyl palladium complexes stabilized by mixed spectator ligands, namely the water soluble sodium 3,3′,3″‐phosphinetriyltribenzenesulfonate, (TPPTS) and three carbenes derived from differently alkylated natural xanthines. In order to explore their potential applications we have tested their catalytic activity in the Suzuki‐Miyaura coupling of para‐bromoacetophenone with phenyl boronic acid, chosen as standard reaction. Only one of the complexes under study displays a remarkable stability in water and catalytic activity. We have therefore undertaken a catalytic investigation. These results are reported in the present paper together with the solid state structural characterization of a silver precursor of the palladium allyl complexes.